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Mitochondrial disorders are caused by a failure of the mitochondria to function properly. Mitochondria have many functions within the cell, including making ATP for cellular energy, participation in apoptosis and making free radicals. To make energy, mitochondria utilize the electron transport chain (ETC) to convert fats, sugars and oxygen into ATP, heat, carbon dioxide and water.
Mitochondrial disorders can be caused by defects in any proteins involved in the electron transport chain. Often multiple ETC defects can cause the similar clinical condition. There are over 1500 genes involved with mitochondrial structure and function. Mutations in over 100 nuclear genes have associated with mitochondrial disorders. Within mitochondrial DNA, there are 37 genes; mutations in these genes have also been associated with mitochondrial disorders. The role of many mitochondria-associated genes in disorders affecting mitochondrial function have still not been fully elucidated. Mitochondrial disorders may also be caused by mitochondrial depletion thus decreasing copy number of mtDNA by mutations in the genes necessary for mtDNA replication.
Because the electron transport chain involves proteins encoded in both the nuclear and mitochondrial genomes, mitochondrial diseases can be inherited in nearly any inheritance pattern. Mitochondrial disorders caused by mutations in nuclear DNA may follow autosomal recessive, autosomal dominant or X-linked recessive inheritance.
Disorders caused by mutations in the mitochondrial DNA (mtDNA) follow a maternal inheritance pattern and a unique set of genetic principles. Because all mitochondria in the developing embryo are derived from the oocyte, mutations are only inherited from the mother.
There may be thousands of copies of mtDNA in a single cell. Each cell can contain different proportions of mutant and normal mtDNAs. When mutated mtDNA coexist with non-mutated mtDNA within a single cell, this condition is known as heteroplasmy. Cells that are made up of purely mutant or purely normal mtDNA are said to be homoplasmic.
When heteroplasmic cells replicate, daughter cells may receive unequal amounts of mutated mtDNA. Over many cell divisions the proportion of mutant mtDNAs can drift. This is random, and variable levels of mutated mtDNA can occur within different tissue types.
When an oocyte is formed from a mother with a mitochondrial DNA mutation, the level of heteroplasmy of that egg is randomly segregated. Two eggs from the same mother may have different proportions of mutated mtDNA, therefore, she could have children with different degrees of severity of disease.
Different amounts of heteroplasmy can be associated with different disease states in different tissue. Therefore, it may require a different amount or threshold of mutated mtDNA in one organ to cause disease than would be required in another organ.
Reactive oxidation species generated by the mitochondria damage mtDNA, generating mutations. Additionally, DNA polymerase gamma, the only polymerase involved in mtDNA replication, has low fidelity, leading to a high mutation rate of mtDNA.
The principles of mitochondrial genetics affect clinical presentation in several ways. For example, a given mitochondrial disorder may be inherited in different patterns. Because of the high mtDNA mutation rate, many cases are sporadic rather than inherited. Additionally, the clinical presentations of mitochondrial diseases are highly variable depending on the degree of heteroplasmy in a certain organ system. For mtDNA diseases, even members of the same family with the same genetic mutations may have vastly different symptoms.
Dysfunction of mitochondria can affect every organ and system. High energy tissues (brain, heart, muscle, renal, endocrine) are particularly affected by mitochondrial disorders. General symptoms may include dementia, blindness, ptosis, external ophthalmoplegia, deafness, seizures, tremors, ataxia, heart failure (cardiomyopathy, cardiac conduction defects), muscle weakness, hypotonia, exercise intolerance and diabetes.
The majority of patients with mitochondrial disorders do not fit a particular syndrome. For many patients, the genetic etiology of their disorder is unknown, and there are many genes yet to be discovered.
The majority of mitochondrial disorders do not fit well within any characterized syndrome. Some of the better characterized mitochondrial disorders are:
MELAS is a progressive disease that usually begins in childhood or adolescence. It affects many body systems and progresses with age. Early symptoms include muscle weakness, headaches, seizures and recurrent vomiting. Lactic acidosis can cause vomiting, fatigue, muscle weakness and pain. Most patients with MELAS will have a stroke-like episode by age 40. Stroke-like episodes can involve seizures, loss of vision, temporary muscle weakness and severe headaches. Over time, many stroke-like episodes can cause brain damage and impair cognitive function. Other symptoms can include ataxia, heart disease and diabetes.
MERRF is a progressive disease that affects multiple systems of the body. In most cases, signs of MERRF appear during childhood or adolescence. Most patients with MERRF have myoclonus. Epileptic seizures, ataxia and peripheral neuropathy are common features. Hearing loss and heart abnormalities sometimes occur. When muscle cells from an affected individual are stained and examined under a microscope, they appear as “ragged-red fibers.”
LHON usually affects people in their early 20s, and it is in more common in males than females. LHON causes sudden, painless loss of central vision in both eyes. In most cases, vision loss is permanent, although some people will have gradual improvement in their vision over time. LHON is often caused by homoplasmic mutations in electron transport chain complex I genes and is inherited in a maternal pattern.
Leigh syndrome is characterized by progressive degeneration of the lower brainstem. Children with this condition develop respiratory abnormalities around 1 to 2 years of age. They may also have ophthalmoplegia, ataxia, peripheral neuropathy, hypotonia and psychomotor regression.
Barth syndrome is a mitochondrial condition that follows X-linked inheritance and primarily affects boys. Symptoms may include dilated cardiomyopathy, skeletal myopathy, short stature, and recurrent infections due to neutropenia.
CPEO is characterized by weakness of the muscles that move the eye. The first signs of this condition often begin in early adulthood and may include ptosis, ophthalmoplegia, myopathy of the arms and legs, and dysphagia. Other symptoms can include hearing loss and ataxia.
Individuals with Kearns-Sayre syndrome have chronic external ophthalmoplegia and pigmentary retinopathy, which can cause loss of vision. Other symptoms of KSS can include cardiac conduction defects, ataxia, elevated protein levels in cerebral spinal fluid, hearing loss, kidney disease, diabetes or slow growth. Some patients with KSS develop dementia. KSS usually affects people under the age of 20.
Patients with this 1555A>G mutation in the 12S rRNA gene can develop pre-lingual or post-lingual hearing loss. If infants with this genotype are treated with aminoglycoside antibiotics, hearing loss develops early in life. Individuals without aminoglycoside exposure may develop hearing loss in adulthood.
Mitochondrial depletion syndrome is caused by a drastic reduction in the amount of mtDNA in the cell. Most cases present in childhood with organ malfunction due to lactic acidosis. The presentation of mitochondrial depletion syndrome can be very different among individuals. Organs that may be affected include the muscles, heart, liver, kidneys and brain.
MNGIE mostly affects the nervous system and digestive system. Symptoms usually begin before age 20. Gastrointestinal dysmotility prevents food from moving through the digestive tract effectively. Gastrointestinal dysmotility can result in symptoms such as feeling full easily, trouble swallowing, nausea and intestinal blockage. Leukoencephalopathy is a hallmark of this condition. Other features of MNGIE can include numbness and weakness of the limbs, weakness of eye muscles and hearing loss.
Patients with this condition may have numbness or tingling in the extremities, muscle weakness, balance problems, hearing loss and vision loss caused by retinitis pigmentosa. Developmental delay and learning disabilities are also seen.
Pearson syndrome is a condition that presents in early childhood. The main features of Pearson syndrome are bone marrow dysfunction and pancreatic insufficiency. Muscle weakness and neurological impairment also may occur. Pearson syndrome is usually fatal, but those who survive often develop symptoms of Kearns-Sayre syndrome.
Symptoms of pyruvate carboxylase deficiency include seizures, lactic acidosis, low blood sugar, failure to thrive, growth retardation and developmental delay.
Patients with pyruvate dehydrogenase deficiency have different symptoms depending on disease onset. Early onset disease results in lactic acidosis (buildup of lactic acid in the body) and brain and kidney abnormalities. Later onset forms result in balance and coordination problems when walking and cognitive decline. Growth delay, low muscle tone, tingling in the extremities and other birth defects can also occur.
POLG1 encodes gamma polymerase for mtDNA synthesis. There are six major clinical disorders which can be caused by mutations in POLG1: Alpers-Huttenlocher syndrome (AHS); childhood myocerebrohepatopathy spectrum (MCHS); myoclonic epilepsy, myopathy and sensory ataxia (MEMSA); ataxia neuropathy spectrum (ANS); autosomal recessive progressive external ophthalmoplegia (arPEO); and autosomal dominant progressive external ophthalmoplegia (adPEO). Mutations in POLG1 have also been associated with MNGIE-like syndrome, MELAS, Parkinson's disease and premature menopause. Individuals with POLG1 mutations are also at significant risk of drug-induced liver failure.
In individuals who present with symptoms characteristic of a specific mitochondrial disorder, molecular genetic testing may be able to confirm the diagnosis. When the clinical presentation is not clear, the diagnostic evaluation may include neuroimaging (CT, MRI), neurophysiological studies (EEG, EMG, MRS), eye examination, a hearing test, measurement of glucose and lactate / pyruvate, cardiac testing (ECG, echocardiogram), muscle biopsy or genetic testing.
The Mitochondrial Disorders Program was established in 2012 at the Cincinnati Children’s Hospital Medical Center and is directed by Taosheng Huang, MD, PhD. The program integrates clinical services, genetic testing and research to improve care for children with mitochondrial disorders.
A comprehensive evaluation in the Mitochondrial Clinic includes a physical examination, diagnostic testing, referral to additional specialists, genetic counseling, interpretation of genetic test results and coordination of continuing medical care.
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